JP2024503909A - Use of melanocortin-4 receptor agonists - Google Patents

Abstract

The present invention provides a compound of formula (1) or its pharmaceutical composition for the prevention or treatment of rare genetic obesity diseases, particularly rare genetic obesity diseases associated with impaired melanocortin 4 receptor (MC4R) pathway. Concerning the use of acceptable salts.

Description

The present invention provides the following formula (1) for the prevention or treatment of rare genetic obesity, particularly rare genetic obesity associated with disorders of the melanocortin-4 receptor (MC4R) pathway.
(wherein R1 is _C2 - _C5 alkyl).

Melanocortin receptors (MCRs) are a type of G-protein coupled receptors (GPCRs), and the main role of G-proteins is to activate second messengers and regulate cellular responses to many physiological stimuli through signal transduction. It is to control. To date, five subtypes of melanocortin receptors have been identified. MC1R is mainly expressed in melanocytes and macrophages, and determines skin and hair color by regulating melanin pigment in melanocytes. MC2R is expressed in the adrenal glands and adipose tissue, and is well known for its function in mediating the regulation of adrenal hormone secretion by adrenocorticotropic hormone in the adrenal glands. Since MC3R, MC4R, and MC5R are expressed not only at nerve ends but also in the brain, they mediate the central nervous effects of melanocortin peptides and influence behavior, learning, memory, appetite, nerve development and regeneration, etc. is known to give. Until now, it has been known that MC3R is involved in erectile dysfunction and inflammatory reactions, and MC4R is involved in obesity and diabetes, and research on the specificity of the action of each receptor is actively conducted (Non-patent Document 1 ). As a result, we found that MC4R is deeply involved in genetic research in obese individuals, and demonstrated that this receptor is important in regulating appetite by showing that knockout mice in which MC4R was deleted develop obesity due to overeating. It has been demonstrated that this role plays a role (Non-patent Documents 2, 3, and 4).

On the other hand, among the anti-obesity drugs developed so far, appetite suppressants that act on the central nervous system are mainstream. Among them, drugs that modulate the action of neurotransmitters (eg, phentermine, mazindol, locaserin, fluoxetine and sibutramine) were mainly used. However, the neurotransmitter modulators have a wide range of effects on a variety of physiological effects in addition to appetite suppression through multiple receptor subtypes. Therefore, these drugs have a major drawback in that they have poor selectivity for each subtype and are accompanied by various side effects when administered for a long period of time. On the other hand, melanocortin agonists are neuropeptides rather than neurotransmitters, and considering that functions other than energy metabolism are normal in MC4R gene knockout (KO) mice, melanocortin agonists have no effect on other physiological functions. It has an advantage as a point of action in that it can induce weight loss only by suppressing appetite without feeding.

MacNeil DJ et al., Eur J Pharmacol 2002, 450, 93 Lu D, Willard D et al., Nature 1994, 371(6500), 799 Huszar D et al., Cell 1997, 88(1), 131 Hinney A et al., J Clin Endocrinol Metab 1990, 84(4), 1483

The present invention is based on the following formula (1)
(wherein R1 is _C2 - _C5 alkyl) or a pharmaceutically acceptable salt thereof is used to treat rare genetic obesity diseases, particularly damaged melanocortin-4 receptor (MC4R). The objective is to provide a use for the prevention or treatment of rare genetic obesity diseases related to the inflammatory pathway.

The present invention provides a therapeutically effective amount of the following formula (1):
The present invention provides a drug for preventing or treating rare genetic obesity diseases, which contains a compound represented by the formula (wherein R1 is _C2 - _C5 alkyl) or a pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical for preventing or treating a rare genetic obesity disease, comprising a therapeutically effective amount of the compound of formula (1) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. A composition is provided.

Furthermore, the present invention provides a method for preventing or preventing rare genetic obesity diseases, which comprises administering a therapeutically effective amount of the compound of formula (1) or a pharmaceutically acceptable salt thereof to a subject in need thereof. Provide a method of treatment.

The present invention also provides the use of the compound of formula (1) or a pharmaceutically acceptable salt thereof in the prevention or treatment of rare genetic obesity diseases.

The present invention will be explained in detail below.

According to one aspect of the present invention, a medicament for preventing or treating rare genetic obesity diseases comprises a therapeutically effective amount of the compound of formula (1) or a pharmaceutically acceptable salt thereof. provided.

According to another aspect of the invention, the prevention of rare genetic obesity diseases comprises a therapeutically effective amount of the compound of formula (1) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. Or a therapeutic pharmaceutical composition is provided.

In one embodiment according to the present invention, the compound of formula (1) has the following formula (2):
N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide.

In another embodiment according to the invention, said pharmaceutically acceptable salt is an inorganic acid such as, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid; tartaric acid, formic acid, citric acid. , organic carboxylic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid; sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid including, but not limited to, acid addition salts formed by; In another embodiment according to the invention, said pharmaceutically acceptable salt may be selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid. In another embodiment according to the invention, said pharmaceutically acceptable salt is a hydrochloride.

In another embodiment according to the present invention, the hydrochloride salt of the compound of formula (1) above can be prepared according to Reaction Scheme 1 below. However, those skilled in the art can prepare compounds of formula (1) by various methods based on the structure of formula (1).
<Reaction scheme 1>
(wherein R2 is C ₁ -C ₅ alkyl, R3 is C ₃ -C ₈ cycloalkyl unsubstituted or substituted with 1 or 2 C ₁ -C ₅ alkyl, R4 and R5 are each independently hydrogen or halogen.)

In another embodiment according to the invention, said rare genetic obesity disease may be associated with an impaired melanocortin-4 receptor (MC4R) pathway. In another embodiment according to the invention, said rare genetic obesity disease associated with an impaired melanocortin-4 receptor (MC4R) pathway may be leptin receptor (LEPR) deficiency. Leptin is a hormone secreted from body fat cells (adipocytes), and the leptin hormone acts on leptin receptors in the hypothalamus, regulating metabolic and appetite homeostasis upstream of the melanocortin-4 receptor (MC4R) pathway. and plays an important role in regulating body weight. Therefore, leptin receptor deficiency can cause severe obesity.

In another embodiment according to the invention, a "therapeutically effective amount" for an individual subject means an amount sufficient to achieve the pharmacological effect described above, ie, a therapeutic effect. The amount of compound may vary depending on the condition and severity of the subject, the mode of administration, and the age of the subject being treated, but can be determined based on the knowledge of those skilled in the art.

In another embodiment according to the invention, the therapeutically effective amount of said compound of formula (1) typically ranges from about 0.1 to 500 mg per day, depending on the frequency and intensity of administration, for example. . Typical daily doses for intramuscular or intravenous administration for adults range from about 0.1 to 300 mg per day, which can be administered in divided doses. Some patients may require higher daily doses.

In the present invention, a "pharmaceutical composition" can contain, in addition to the active ingredient according to the present invention, other ingredients such as carriers, diluents, excipients, etc. Accordingly, the pharmaceutical composition may optionally contain a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof. Pharmaceutical compositions facilitate administration of compounds into the body. Various methods for administering compounds include, but are not limited to, oral, injection, aerosol, parenteral, and topical administration.

As used herein, "carrier" refers to a compound that facilitates introduction of a compound into a cell or tissue. For example, dimethyl sulfoxide (DMSO) is a conventional carrier that facilitates the introduction of many organic compounds into the cells or tissues of an organism.

As used herein, "diluent" refers to a compound that is diluted in a solvent that not only stabilizes the biologically active form, but also dissolves the compound. In this field, salts dissolved in buffers are used as diluents. The conventionally used buffer is phosphate buffered saline, which mimics the form of salts in body fluids. Buffers can control the pH of a solution at low concentrations, so that buffer diluents do not significantly alter the biological activity of the compound.

As used herein, "pharmaceutically acceptable" means a property that does not impair the biological activity or physical properties of the compound.

Compounds according to the invention can be formulated as a variety of pharmaceutically administered dosage forms. In preparing the pharmaceutical composition of the present invention, the active ingredient, specifically the compound of formula (1) or a pharmaceutically acceptable salt thereof, is added to a pharmaceutically acceptable salt selected in consideration of the dosage form to be prepared. Mix with carrier. For example, the pharmaceutical composition according to the present invention can be formulated as an injection, an oral preparation, etc., if necessary.

The compounds of the invention can be formulated in conventional manner using known pharmaceutical carriers and excipients and placed in single or multiple unit containers. The formulations may be solutions, suspensions, or emulsions in oil or aqueous solvents and include conventional dispersing, suspending, or stabilizing agents. Additionally, the compounds may be in dry powder form, for example, to be dissolved in sterile, pyrogen-free water before use. Compounds of the invention can be formulated into suppositories using conventional suppository bases such as cocoa butter and other glycerides. Solid forms for oral administration include capsules, tablets, pills, powders and granules. Particularly preferred are capsules and tablets. Preferably, the tablets and pills are enteric coated. Solid forms can be prepared by mixing the compounds of the invention with at least one carrier selected from inert diluents such as sucrose, lactose or starch, lubricants such as magnesium stearate, disintegrants, binders and the like. It can be prepared. They may also be formulated as transdermal dosage forms, such as lotions, ointments, gels, creams, patches or sprays. In another embodiment according to the invention, the medicament or pharmaceutical composition may be an oral formulation.

As used herein, the term "prevention" means reducing or eliminating the possibility of contracting a disease.

As used herein, the term "treatment" means to prevent, slow, or ameliorate the progression of a disease in a subject exhibiting symptoms of the disease.

The medicament or pharmaceutical composition according to the invention can efficiently prevent or treat rare genetic obesity diseases, especially rare genetic obesity diseases associated with an impaired melanocortin-4 receptor (MC4R) pathway.

It is a graph showing the results of measuring the weight reduction effect in a leptin receptor-deficient mouse model (db/db mouse model).

Hereinafter, the present invention will be explained in more detail with reference to the following examples. However, it should be understood that the scope of protection of the present invention is not limited to these examples.

Production example: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- Synthesis of carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide hydrochloride
The title compound was obtained through the following steps A, B, C and D.

Step A: Methyl (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s, Preparation of 4R)-4-methylcyclohexyl)isobutyramide)pyrrolidine-2-carboxylate Methyl(2S,4S)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramide)pyrrolidine-2- Carboxylate hydrochloride (28.7g, 82.73mmol), (3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid (24.5g, 86.87mmol) , 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.2 g, 115.83 mmol) and 1-hydroxybenzotriazole hydrate (15.7 g, 115.83 mmol) in N,N'- Dissolved in dimethylformamide (400 mL) and slowly added N,N'-diisopropylethylamine (72.0 mL, 413.66 mmol). After stirring at room temperature for 16 hours, the reaction solvent was concentrated under reduced pressure, a 0.5N aqueous sodium hydroxide solution was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with an aqueous sodium chloride solution and water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound (41.19 g, 87%).
MS [M+H] = 575 (M+1)

Step B: (2S,4S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R) ) -4-Methylcyclohexyl)isobutyramido)pyrrolidine-2-carboxylic acid Preparation of methyl(2S,4S)-1-((3S,4R)-1-(tert-butyl)-4 obtained in the above step A) -(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramide)pyrrolidine-2-carboxylate (39.4 g, 68.62 mmol) in methanol (450 mL), and 6N aqueous sodium hydroxide solution (57.2 mL, 343.09 mmol) was added. After stirring at room temperature for 16 hours and adjusting the pH to about 5 with a 6N aqueous hydrochloric acid solution, the reaction solution was concentrated under reduced pressure. The concentrated solution was dissolved in dichloromethane, and the insoluble solids were filtered through filter paper. The filtrate was concentrated under reduced pressure to obtain the crude product (38.4 g, 99%), which was used in the next step without purification.
MS [M+H] = 561 (M+1)

Step C: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- Preparation of carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide (2S,4S)-1-((3S,4R)-1 obtained in step B above -(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-4-(N-((1s,4R)-4-methylcyclohexyl)isobutyramide)pyrrolidine-2-carboxylic acid (38. 4g, 68.60mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (18.4g, 96.04mmol) and 1-hydroxybenzotriazole hydrate (13.0g, 96.04mmol) was dissolved in N,N'-dimethylformamide (200 mL), and morpholine (5.9 mL, 68.80 mmol) and N,N'-diisopropylethylamine (59.7 mL, 343.02 mmol) were slowly added sequentially. After stirring at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure, 0.5N aqueous sodium hydroxide solution was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with an aqueous sodium chloride solution and water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain the title compound (37.05 g, 86%).
MS [M+H] = 630 (M+1)

Step D: N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- Preparation of N-((3S,5S)-1-((3S, carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide hydrochloride obtained in step C above ,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R) -4-Methylcyclohexyl)isobutyramide (5.0 g, 7.95 mmol) was dissolved in ethyl acetate (50 mL), and a 2N hydrochloric acid solution in ethyl acetate (3.97 mL, 15.89 mmol) was slowly added. After stirring at room temperature for 30 minutes, the reaction solvent was concentrated under reduced pressure. The resulting crude solid was purified by trituration with hexane and diethyl ether to yield the title compound (5.23 g, 99%).
MS [M+H] = 630 (M+1)
¹ H NMR (500 MHz, CD ₃ OD) δ 7.49-7.44 (m, 4H), 4.83 (m, 1H), 4.23-4.20 (m, 1H), 3.95-3.91 (m, 2H), 3.79-3.47 ( m, 14H), 3.03-3.00 (m, 1H), 2.86-2.82 (m, 1H), 2.73-2.67 (m, 1H), 2.20-2.14 (m, 1H), 1.97 (m, 1H), 1.80- 1.62 (m, 5H), 1.50 (s, 9H), 1.44-1.27 (m, 3H), 1.06-1.04 (m, 9H)

Example: db/db mouse model experiment The db/db mouse, which has a mutation in the leptin receptor gene that acts upstream of the melanocortin-4 receptor (MC4R), is a model that reflects receptor receptor-deficient obesity; Mice exhibit abnormal phenotypes associated with metabolic diseases, including bulimia and severe obesity. To confirm the anti-obesity effect, db/db mice, a genetic obese mouse model with a mutation in the leptin receptor related to the MC4R pathway, were fed a 45kcal% high-fat diet (45kcal% fat diet). , N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-( Morpholine-4-carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide hydrochloride (hereinafter referred to as 'test compound') was repeatedly administered for 4 weeks. The weight gain suppressing effect was measured by measuring body weight during the administration period, and the body fat mass reducing effect was confirmed by measuring the total body fat mass after repeated administration for 4 weeks. As a result, body weight and weight gain rate were significantly reduced compared to the negative control group. As a result of body fat analysis, there was no difference in fat-free mass compared to the negative control group, whereas body fat mass was significantly decreased compared to the negative control group. The results are shown in FIG.

As can be seen from FIG. 1, it was confirmed that the test compound of the present invention exhibited a significant weight loss effect.

Claims (12)

The following formula (1) for therapeutically effective amount:
(In the formula, R1 is _C2 - _C5 alkyl.) A drug for preventing or treating rare genetic obesity diseases, comprising a compound represented by the formula or a pharmaceutically acceptable salt thereof. The compound of the formula (1) is represented by the following formula (2)
N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- The drug according to claim 1, which is carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide. 2. Medicament according to claim 1, characterized in that the pharmaceutically acceptable salt is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid. Medication according to claim 1, characterized in that said rare genetic obesity disease is associated with an impaired melanocortin-4 receptor (MC4R) pathway. Medication according to claim 4, characterized in that the rare genetic obesity disease associated with an impaired melanocortin-4 receptor (MC4R) pathway is leptin receptor (LEPR) deficiency. The drug according to claim 1, which is an oral drug. The following formula (1) for therapeutically effective amount:
(wherein R1 is _C2 - _C5 alkyl) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, for prevention of rare genetic obesity diseases or a therapeutic pharmaceutical composition. The compound of the formula (1) is represented by the following formula (2)
N-((3S,5S)-1-((3S,4R)-1-(tert-butyl)-4-(4-chlorophenyl)pyrrolidine-3-carbonyl)-5-(morpholine-4- The pharmaceutical composition according to claim 7, which is carbonyl)pyrrolidin-3-yl)-N-((1s,4R)-4-methylcyclohexyl)isobutyramide. 8. A pharmaceutical composition according to claim 7, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid. Pharmaceutical composition according to claim 7, characterized in that said rare genetic obesity disease is associated with an impaired melanocortin-4 receptor (MC4R) pathway. Pharmaceutical composition according to claim 10, characterized in that the rare genetic obesity disease associated with an impaired melanocortin-4 receptor (MC4R) pathway is leptin receptor (LEPR) deficiency. The pharmaceutical composition according to claim 7, which is an oral preparation.